1. Field of the Invention
The present invention relates to a novel arylsulfonylimidazolone derivative that exhibits potent antineoplastic activity. More specifically, the present invention relates to a novel arylsulfonylimidazolone derivative represented by the following formula (I) which shows a superior antineoplastic activity in contrast to the known sulfonylurea antitumor agents as well as little side effect: ##STR2## its pharmaceutically acceptable salt or stereoisomer, in which ---- represents single or double bond,
R.sub.1 represents hydrogen or methyl, PA1 R.sub.2 represents chloroacetyl; C.sub.1 -C.sub.5 alkylaminoacetyl; allylaminoacetyl; C.sub.1 -C.sub.4 alkoxycarbonyl; nicotinyl; furanoyl; thiophenoyl; benzoyl which can be substituted by halogen, nitro, cyano, amino which can be substituted by nonpolar amino acid residue, hydroxy, methyl or methoxy which can be independently of one another substituted by halogen, ethoxy or chloroacetylamino; or ##STR3## (wherein, X represents oxygen or sulfur atom, R.sub.3 represents C.sub.1 -C.sub.4 alkyl, allyl, chloroacetyl or cyclohexyl, or phenyl which can be substituted by methoxy, fluoro, methyl, amino or methylthio). PA1 R.sub.1 represents hydrogen or methyl, PA1 R.sub.2 represents chloroacetyl; C.sub.1 -C.sub.5 alkylaminoacetyl; allylaminoacetyl; C.sub.1 -C.sub.4 alkoxycarbonyl; nicotinyl; furanoyl; thiophenoyl; benzoyl which can be substituted by halogen, nitro, cyano, amino which can be substituted by nonpolar amino acid residue, hydroxy, methyl or methoxy which can be independently of one another substituted by halogen, ethoxy or chloroacetylamino; or ##STR6## (wherein, X represents oxygen or sulfur atom, R.sub.3 represents C.sub.1 -C.sub.4 alkyl, allyl, chloroacetyl or cyclohexyl, or phenyl which can be substituted by methoxy, fluoro, methyl, amino or methylthio). PA1 a) a compound represented by the following formula (III): ##STR7## is reacted with a compound represented by the following formula (IV): EQU R.sub.2 --Y (IV) PA1 to provide the compound represented by the following formula (I): ##STR8## in the above formulas, R.sub.1 and R.sub.2 are each as previously defined, and Y represents a reactive leaving group; or PA1 b) a compound represented by the following formula (III) or its salt: ##STR9## is reacted with a compound represented by the following formula (V) EQU R.sub.3 NC.dbd.X (V) PA1 to provide a compound represented by the following formula (Ia): ##STR10## in the above formulas, R.sub.1, R.sub.3 and X are each as previously defined; or PA1 c) a compound represented by the following formula (Ib) having a p-nitrobenzoyl group at 1-position of indoline group: ##STR11## is reduced to provide a compound represented by the following formula (Ic): ##STR12## the compound of formula (Ic) or its salt thus prepared is condensed with an amino acid wherein the amino group is protected by t-butoxycarbonyl represented by the following formula (VI): EQU R.sub.4 --tBOC (VI), PA1 and then deprotected to provide a compound represented by the following formula (Id): ##STR13## in the above formulas, tBOC represents t-butoxycarbonyl and R.sub.4 represents nonpolar amino acid residue. PA1 a) ---- is single or double bond, R.sub.1 is hydrogen or methyl, and R.sub.2 is chloroacetyl; C.sub.1 -C.sub.5 alkylaminoacetyl; allylaminoacetyl; C.sub.1 -C.sub.4 alkoxycarbonyl; nicotinyl; furanoyl; thiophenoyl; or benzoyl which can be substituted by halogen, nitro, cyano, hydroxy, methyl or methoxy which can independently of one another be substituted by halogen, ethoxy or chloroacetylamino, PA1 b) ---- is single or double bond, R.sub.1 is hydrogen, and R.sub.2 is ##STR14## (wherein, X is oxygen or sulfur atom, and R.sub.3 is C.sub.1 -C.sub.4 alkyl, allyl, chloroacetyl or cyclohexyl, or phenyl which can be substituted by methoxy, fluoro, methyl, amino or methylthio), and PA1 c) ---- is single bond, R.sub.1 is hydrogen, R.sub.2 is ##STR15## (wherein, R.sub.4 is hydrogen or nonpolar amino acid residue), and having (S)-stereoisomeric configuration at 4-carbon of imidazolone ring bearing the phenyl group. PA1 d) a compound represented by the following formula (VIIa): ##STR19## is reacted with a compound represented by the following formula (VIII): ##STR20## to provide a compound represented by the following formula (IXa): ##STR21## then the trifluoroacetyl group as an amino-protecting group of the compound of fomula (IXa) is removed to prepare the compound represented by the following formula (IIIa): ##STR22## in the above formulas, R.sub.1 is as previously defined; or e) a compound represented by the following formula (VIIb): ##STR23## is reacted with a compound represented by the following formula (VIII): ##STR24## to provide a compound represented by the following formula (IXb): ##STR25## then the trifluoroacetyl group of the compound of fomula (IXb) is removed and the product thus obtained is acid-hydrolyzed to prepare the compound represented by the following formula (IIIb): ##STR26## in the above formulas, R.sub.1 is as previously defined; or f) (S)-phenylglycinol represented by the following formula (X): ##STR27## is reacted with phenylchloroformate (ClCOOPh) to provide a compound represented by the following formula (XI): ##STR28## which is reacted with methanesulfonylchloride (CH.sub.3 SO.sub.2 Cl) to produce a compound represented by the following formula (XII): ##STR29## then the compound of formula (XII) thus obtained is combined with a compound represented by the following formula (XIII): ##STR30## and deprotected to provide a compound represented by the following formula (IIIc): ##STR31## in the above formulas, R.sub.1 is as previously defined.
The present invention also relates to a process for preparing the compound of formula (I), a novel intermediate which can be used for preparing the desired compound of formula (I), and an antitumor composition that includes the compound of formula (I) as an active ingredient.
2. Background Art
Many sulfonylureas that exhibit different kinds of activities from each other have been known in the art. Some of them have hypoglycemic activities, some of them have herbicidal activities, and some of them have antimycotic activities.
In recent years, it has also been reported in several literatures that certain diarylsulfonylureas have antineoplastic activity (see, U.S. Pat. No. 4,845,128(1989); European Patent Publication No. 0222475 (published on May 20, 1987); European Patent Publication No. 0291269 (published on Nov. 17, 1988); European Patent Publication No. 0467613 (published on Jan. 22, 1992); Grindey, et al., American Association of Cancer Research, 27:277 (1986); Houghton, et al., Cancer Chemotherapy and Pharmacology, 25:84-88 (1989)).
SulofenurN-(indan-5-sulfonyl)-N-(4-chlorophenyl)urea; LY186641! represented by the following formula (II) is a typical example of the known antineoplastic diarylsulfonylurea compounds and it has progressed to Phase I clinical trials(see, Cancer Res., 49, 5217-5220, 1989): ##STR4## Particularly, it has been reported that this compound exhibits potent antitumor activity upon solid tumors which is hard to cure(see, J. Med. Chem., 1990, 33, 2393). Although the mechanism of action of this compound has not known yet, it has an exceptionally broad spectrum of activity upon solid tumors and human tumor xenogafts and also has some other clinical activities. Moreover, Sulofenur does not produce serious side effects including myelosuppression, nausea, vomiting, alopecia, mucositis, and hepatotoxicity which may be commonly encountered when other antineoplastic agents are used, but only shows minor side effects such as anemia or methemoglobinemia which are originated from aniline class of metabolite.